Hypoxia, a common feature of most
solid tumors, causes severe tumor
resistance to chemotherapy and immunotherapy. Herein, a tumor-acidity
and bioorthogonal chemistry-mediated on-site size transformation clustered
nanosystem is designed to overcome hypoxic resistance and enhance
chemoimmunotherapy. The nanosystem utilized the tumor-acidity responsive
group poly(2-azepane ethyl methacrylate) with a rapid response rate
and highly efficient bioorthogonal click chemistry to form large-sized
aggregates in tumor tissue to enhance accumulation and retention.
Subsequently, another tumor-acidity responsive group of the maleic
acid amide with a slow response rate was cleaved allowing the aggregates
to slowly dissociate into ultrasmall nanoparticles with better tumor
penetration ability for the delivery of doxorubicin (DOX) and nitric
oxide (NO) to a hypoxic tumor tissue. NO can reverse a hypoxia-induced
DOX resistance and boost the antitumor immune response through a reprogrammed
tumor immune microenvironment. This tumor-acidity and bioorthogonal
chemistry-mediated on-site size transformation clustered nanosystem
not only helps to counteract a hypoxia-induced chemoresistance and
enhance antitumor immune responses but also provides a general drug
delivery strategy for enhanced tumor accumulation and penetration.
Opening the source code to a software product often implies that consumers would not pay for the software product itself. However, revenues may be generated from
We examine the use of consumer cash mail‐in rebates offered by a manufacturer in a Stackelberg game where the manufacturer is the leader and the retailer is the follower. Our analysis indicates that rebates are profitable for manufacturers if consumers are inconsistent in the sense that their rebate valuation when they make purchase decisions is independent of their redemption probabilities when they make redemption decisions. If the manufacturer keeps the wholesale price unchanged, then the rebate increases the retailer's profit by a larger amount than the increase in the manufacturer's profit. If the manufacturer jointly optimizes the wholesale price and rebate, then the increase in the manufacturer's profit is twice the increase in the retailer's profit. The retailer responds to rebates by increasing the retail price, which increases the margin paid by consumers who do not redeem the rebate. On average, consumer surplus decreases when it is optimal for manufacturers to offer rebates. We suggest incentive schemes that make it worthwhile for retailers to limit the price increase. In these incentive schemes, the manufacturer imposes a negative relationship between the rebate value and the retail price. We show that such incentives increase supply chain profits.
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